7-{8 2-(N-amino amidinothio)acetamido{9 cephalosporanic acids

ABSTRACT

D R A W I N G The anti-bacterial agents of the invention present the following structural formula:     in which R is a member selected from the group consisting of -H, alkanoyl of 2 to 6 carbon atoms, phenyl, and when n is zero, alkylidene of 3 to 6 carbon atoms and pyridylmethylene; R2 is a member selected from the group consisting of -H, alkanoyloxy or 2 to 6 carbon atoms,   OR WHEN TAKEN WITH THE 3-CARBOXYL GROUP   R3 is a member selected from the group consisting of -H, alkyl of 1 to 6 carbon atoms and aryl of 6 to 8 carbon atoms; M is a member selected from the group consisting of -H, an alkali metal and -NH4; n is 0 or 1; and THE PHARMACEUTICALLY ACCEPTABLE HYDROHALIDE ADDITION SALTS THEREOF.

United States Patent 1191 Wei [ Sept. 23, 1975 7-[2-(N-AMINOAMIDINOTHIO)ACETAMIDO1CEPHALOS- PORANIC ACIDS [75] Inventor: Peter H. L.Wei, Springfield, Pa.

[73] Assignee: American Home Products Corporation, New York, NY.

221 Filed: Mar. 18, 1974 21 Appl. No.: 452,088

52 U.S. Cl. 260/243 c; 424/246 51] Int. c1. CO7 D 501/28, CO7 D 501 /22,

CO7 D 501/40, A61K 31/545 [58] Field of Search 260/243 c, 240 G [56]References Cited UNITED STATES PATENTS 2/1972 Crast, Jr 260/243 C10/1974 Breuer et al. 260/243 C Primary Examiner-Donald G. DausAssistant Examiner-Diana G. Rivers Attorney, Agent, or FirmRichard K.Jackson [57] ABSTRACT The anti-bacterial agents of the invention presentthe following structural formula:

N -SJL L CH S 1,1:

or when taken with the 3-carboxyl group R is a member selected from thegroup consisting of H, alkyl of l to 6 carbon atoms and aryl of 6 to 8carbon atoms;

M is a member selected from the group consisting of l-l, an alkali metaland NH n is O or 1; and

the pharmaceutically acceptable hydrohalide addition salts thereof.

7 Claims, No Drawings n x I 01) NHC-SCHCONH n l 'co .M

in which R is a member selected from the group consisting of H, alkanoylof 2 to 6 carbon atoms, phenyl, and when n is zero, alkylidene of 3 to 6carbon atoms and pyridylmethylene;

with an appropriately substituted .7-(2-haloacetamido) cephalosporinderivative. The reaction occurs at ambient temperature in an inert polarorganic solvent such as acetone or dimethylformamide to yield thehydrohalide salt of the 7-[2-(N-aminoamidinothio) acetamido]cephalosporanic acid derivative. The preparation of each ofthesemicarbazones and semicarbazides, as well CHZRZ as the7-(2-haloacetamido) cephalosporin derivatives is known in the chemicalliterature. 7

The preferred group of compounds. from the standpoint of availability ofthe reactants. ease of reaction and production economies. are those ofthe formula:

=1; nrwntm mi i': sea CONH R is a member selected from the groupconsisting of --H.-alkanoyloxy of- 2 to 'carbon atoms.

. i l -S-n S CH3 es a or when taken with the 3- carb oxy group thepharmaceutically acceptable hydrohalide addition saltsther'eof.

The term "alkyl". as it is used herein. isintended to .cmb'raceunivalentaliphatic hydrocarbons containing from I to 6 carbon atoms such as.methyl; ethyl. propyl. i-propyl. butyl. i'-butyl,'amyl and hexyl; Theterm aryl" is intended to embrace univalent aromatic hydrocarbonscontaining 6 to 8 carbon atoms such phenyl.

tolylbethylphenyl and di-methylphenyl. The compounds ofthis-inventionare prepared'by reacting the appropriately substituted thiosemicarbazone:or thiosemicarbazide ofth'e formula: t

CO M

in which R is a member selected from the group consisting of H, acetyl.phenyl and when n is 0. isopropylidene and 4-pyridylmethylene; R is amember selected from the group consisting of H and acetoxy;

X is C1 or Br; and

n is 0 or 1.

The compounds of this invention have been found to be activeanti-bacterial agents effective against grampositive and gram-negativetest organisms as well as penicillin resistant staphlococcus, by usingthe well known and scientifically accepted agar serial dilution testingtechnique. Thus, the compounds of this invention are useful in thefields of comparative pharmacology and in microbiology and for thetreatment of bacterial infections amenable to treatment with penicillinand cephalosporin antibiotics.

The following examples illustrate the preparation of representativecephalosporin derivatives. The compounds produced in the followingexamples are generally recovered in the hydrohalide addition salt form.frequently with a small amount of solvent. the latter being readilyremoved by further vacuum stripping of the product. The free bases arereadily formed by neutralization of the hydrohalide. by conventionaltechniques. The activity of each exemplified product is presented forthose specific bacterial strains against which the compound exemplifiedwas active at or below 250 micrograms per milliliter. The representativenature of the bacterial strains employed to demonstrate anti-bacterialactivity are indicative of the broader applicability of the compounds ofthis invention in the control of bacterial infestations other than thosespecifically referred to in each of the following examples. The bacteriaare named followed by the specific strain and the concentration inmicrograms per milliliter at which 100 percent inhibition occurred. Theabbreviations for each bacterium are:

BA SU Bacillus xumilis 130 13R Burdelella hrmu'lzis'eplicu ES COEst'lu'rit'lziu cull ES 1N Escherichia inu'rmediu HF. SP Hercllt'uspecies KL PN Klebxivllu pneunmniuz' NF. CA Neisscriu cularrlzulis PR VUIrau'us vulgaris SA PA Salmonella paralyplii ST AU Slap/1 ylucuccusuureus EXAMPLE I 7-12-( N-Acetamidoamidinothio)acetamido]cephalosporanicacid hydrobromide.

An acetone solution of aeetylthiosemicarbazide (0.27 gram. 2 millimole)and 7-(2- bromoacetamido)cephalosporanic acid (0.78 gram, 2 millimole)was stirred at room temperature overnight. After a small amount ofinsoluble material was filtered, the solvent was removed. The solidresidue (0.7 gram) was treated with diethyl and ether and collected.

Elemental Analysis for C, H, N O;S .HBr.(C H O: Calcd: C, 37.99; H,5.04; N, 11.66. Found: C, 38.31; H, 4.76; N. 11.37.

7-[ 2-( N-Anilinoamidinothio )acetamido1cephalosporanic acidhydrobromide.

The title compound was prepared by following the procedure of Example 1.except that phenylthiosemicarbazide was utilized.

Elemental Analysis for C ,,H ,N F,O,;S .HBr: Calcd: C. 40.70; H, 3.96;N, 12.49. Found: C, 40.30; H, 3.95; N, 11.88.

BA 51 6633 .976 B BR 4617 250 ES (0 9637 125 133 IN 65-1 250 111-: SP9955 62.5 Kl. PN 10031 250 NE (A 8193 125 PR V1. 61196 125 SA PA 1173762.5 S'l All (15381 3.90 ST AU SMITH 3.90 ST Al, CHP 7.81 ST AU 53-18015.6

EXAMPLE 111 7-[ 2-(N- isopropylideneaminoamidinothio)acetamidolcephalosporanic acid hydrobromide.

BA SU 6633 .244 B0 BR 4617 62.5 ES (0 9637 31.3 Hl-I SP 9955 62.5 Kl. PN10031 31.3 NE CA 14193 625 PR vU 6896 313 5A PA 11737 15.6 ST AU 653x?.976 ST AU SMITH .976 ST AU CHP 1.95 H Al. 53-1140 1.95

EXAMPLE 1V w 7-[2-(Aminoamidinothio)acetamido]cephalosporanic acidhydrobromide The title compound was prepared by following the procedureof Example 1. except that thiosemicarbazide was utilized. ElementalAnalysis for C, ,H,;N,,O,;S .HBr.C-

H -,OCH CH-,OCH;,: Calcd: C, 35.59; H, 4.75; N, 12.21. Found: C, 35.64;H, 4.27; N, 11.39.

BA SU 6633 .488 ST AU 6531 P 1.95 sT AU SMITH .976 ST AU CHP 7.81 ST AU53-1x0 3.90 NE CA 8193 125 SA PA 11737 31.3 Kl. PN 10031 62.5 BO BR 4617125 PR vU 6896 125 HE SP 9955 250 EXAMPLE V2-(4-Pyridylmethylenehydrazinoimidocarbonylthio)acetamidocephalosporanic acid hydrobromide.

The thiosemicarbazone of 4-pyridylcarb0xaldehyde (0.36 gram. 2millimole) and 7- (bromoacetamido)cephalosporanic acid (0.78 gram, 2millimole) were dissolved in dimethylformamide. and

69 the solution was stirred at room temperature for 2 hours. After thesolvent was removed in vacuo below 30C. the residue was treated withacetone. The product which appeared as a polymorphous solid. weighed0.55 gram. On concentration of this filtrate an addi-' tional 0.5 gramof product was recovered.

Elemental Analysis for C,,,H ,,N O S .HBr.3H O: Calcd: C, 37.66; H,5.03; N, 13.97. Found: C, 37.66; H, 4.021N. 14.01. i

BA SL' 6633 .488 ST AU 6538f .976 ST AU SMITH .976 ST AU CHP 3.90 ST AU53-l8l) 3.90 NF. CA EH93 62.5 SA PA H737 3L3 Kl. PN l()()3l 3L3 What isclaimed is: 1. A compound of the formula:

M is a member selected from the group consisting of -H. an alkali metaland -NH.,; n is (l or i; and

ythe pharmaceutically acceptable hydrohalide addition salts thereof.

0/ CH R in which R is a member selected from the group consisting of -H.acetyl or phenyl. when n is l. and isopropylidene or 4-pyridylmethylene.when n is zero; R is a member selected from the group consisting of --Hand acetoxy'.

X is --Cl or -Br; and

n is 0 or i.

3. The compound of claim 1 which is 7-[2-(N-acetamidoamidinothio)acetamido]cephalosporanic acid and the hydrohalideaddition salts thereof.

4. The compound of claim 1 which is 7-[2-(N-anilinoamidinothio)acetamido]cephalosporanic acid and the hydrohalideaddition salts thereof.

5. The compound of claim 1 which is 7-[2-(N-isopropylideneaminoamidinothio)acetamido1cephalosporanic acid and thehydrohalide addition salts thereof.

6. The compound of claim 1 which is 7-[2-aminoamidinothio)acetamidolcephalosporanic acid and the hydrohalideaddition salts thereof.

7. The compound of claim 1 which is 2-(4-pyridylmethylenehydrazinoimiclocarbonylthio)acetamido cephalosporanicacid and the hydrohalide addition salts thereof.

1. A COMPOUND OF THE FORMULA:
 2. A compound of claim 1 of the formulA:3. The compound of claim 1 which is7-(2-(N-acetamidoamidinothio)acetamido) cephalosporanic acid and thehydrohalide addition salts thereof.
 4. The compound of claim 1 which is7-(2-(N-anilinoamidinothio)acetamido) cephalosporanic acid and thehydrohalide addition salts thereof.
 5. The compound of claim 1 which is7-(2-(N-isopropylideneaminoamidinothio)acetamido) cephalosporanic acidand the hydrohalide addition salts thereof.
 6. The compound of claim 1which is 7-(2-aminoamidinothio)acetamido)cephalosporanic acid and thehydrohalide addition salts thereof.
 7. The compound of claim 1 which is2-(4-pyridylmethylenehydrazinoimidocarbonylthio)acetamidocephalosporanic acid and the hydrohalide addition salts thereof.